This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HYPOTHESIS In HIV patients with HAART-associated dyslipidemia , an intensive lifestyle intervention with diet and exercise can: A. Convert the lipid profile from atherogenic to cardioprotective; B. Decrease abdominal visceral fat mass; C. Improve hormonal, metabolic and lipoprotein markers associated with insulin resistance. SPECIFIC AIMS 1. To compare the effects of 1) usual care, 2) intensive diet and exercise intervention (DE), 3) DE + niacin, 4) DE + fenofibrate, and 5) DE + niacin + fenofibrate on fasting plasma triglyceride concentrations (Primary endpoint). (To achieve this Aim, we will recruit 240 HIV patients with hypertriglyceridemia who are on stable HAART regimens. We will assign them randomly to the five placebo-controlled treatment protocols (48 per group) and measure fasting plasma concentrations of triglycerides (primary lipid endpoint) as well as fasting plasma concentrations of HDL cholesterol, total cholesterol and LDL cholesterol (secondary lipid endpoints) at baseline and after 6 months of intervention.) 2. To compare the effects of the five treatment protocols on body fat distribution. (To achieve this Aim, we will measure, in the same subjects and at the same time points, regional fat distribution (ratio of abdominal visceral adipose mass to subcutaneous adipose mass) using computerized tomography.) 3. To compare the effects of the five treatment protocols on hormonal, lipoprotein and metabolic markers of insulin resistance. (To achieve this Aim, we will measure, in the same subjects, changes in the plasma concentrations of insulin, glucose, leptin, free fatty acids, and LDL and HDL subfractions, in the compositions of LDL and HDL, and in the activity of cholesteryl ester transfer protein.) BACKGROUND AND SIGNIFICANCE Highly active anti-retroviral therapy (HAART) is associated with dyslipidemia and insulin resistance in a large proportion of HIV-infected patients, and with anthropomorphic changes (lipoatrophy, central obesity) in a smaller subset. The dyslipidemia and insulin resistance place these patients at increased risk for cardiovascular disease. The mechanisms leading to the dyslipidemia, insulin resistance and anthropomorphic changes - collectively termed "HIV-lipodystrophy" - have been unclear. Numerous small studies have failed to delineate a course of therapy that can clearly reverse the dyslipidemia and attendant cardiovascular risk in the majority of patients. There is an urgent need for evidence-based, rational, effective therapy of this condition. Based on 1) our recent data on key mechanisms of altered lipid kinetics in HIV-lipodystrophy (specifically, elevated rates of lipolysis, inadequate fatty acid oxidation, and increased hepatic reesterification of triglycerides);2) evidence that diet and exercise patterns of HIV patients are suboptimal to manage cardiovascular risk factors;and 3) the latest treatment recommendations for dyslipidemia and insulin resistance, we propose a randomized, placebo-controlled trial of intensive lifestyle modification and two lipid-lowering agents (niacin and fenofibrate). The long-term objective is to develop effective, safe, rational treatment of HIV-associated dyslipidemia and lipodystrophy.